5-bromo-indirubins

Patent metadata

Field	Value
Publication number	US-2018170870-A1
Application number	US-201815893488-A
Country	US
Kind code	A1
Filing date	Feb 9, 2018
Priority date	Mar 14, 2014
Publication date	Jun 21, 2018
Grant date	—

Abstract

Disclosed herein are compositions and methods for treating cancer, FLT3-AML, and CML.

First claim

1 . A compound having formula:

wherein
R 50 is hydrogen, oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CH2COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , or unsubstituted alkyl;
R 51 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NR 51A R 51B , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, or unsubstituted heteroalkyl;
R 51A and R 51B are independently hydrogen or unsubstituted alkyl;
R 52 is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl;
z1 and z2 are independently 0, 1, 2, 3, 4, or 5,
including pharmaceutically acceptable salts thereof.

2 . - 14 . (canceled)

15 . A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound having formula:

or a pharmaceutically acceptable salt thereof;
wherein:
R 50 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , or unsubstituted alkyl;
R 51 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NR 51A R 51B , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, or unsubstituted heteroalkyl;
R 51A and R 51B are independently hydrogen or unsubstituted alkyl;
R 52 is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl; and
z1 and z2 are independently 0, 1, 2, 3, 4 or 5.

16 . (canceled)

17 . The method of claim 15 , wherein said cancer is cancer is lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, or prostate cancer.

18 . (canceled)

19 . A method of treating CML expressing an ABL1-kinase, said method comprising administering an effective amount of a compound of claim 1 .

20 . The method of claim 19 , wherein said ABL1-kinase is a ABL1 mutant-kinase.

21 . The method of any one of claims 19 to 20 , wherein said ABL1 mutant-kinase is a BCR-ABL1 mutant kinase.

22 . - 24 . (canceled)

25 . A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound having the formula:

wherein,
L is a bond or substituted or unsubstituted alkylene;
R 1 is —NR 2 R 3 ;
R 2 and R 3 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein R 2 and R 3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
R 5 and R 6 are independently hydrogen or halogen; or pharmaceutically acceptable salts thereof, thereby treating said acute myeloid leukemia.

26 . - 31 . (canceled)

32 . The method of claim 25 , wherein R 2 and R 3 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

33 . - 42 . (canceled)

43 . A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound according to claim 25 , thereby treating said acute myeloid leukemia.

44 . - 45 . (canceled)

46 . The method of claim 43 , wherein said FLT3-kinase is a FLT3-mutant kinase.

47 . The method of claim 46 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase.

48 . The method of claim 47 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, 1836, D839, S840, N841, or Y842 of SEQ ID NO:1.

49 . The method of claim 46 , wherein said FLT3-mutant kinase comprises a FLT3-ITD mutant kinase.

50 . - 51 . (canceled)

54 . A method of modulating activity of a FLT3-kinase, said method comprising contacting a FLT3-kinase with a compound having formula:

wherein,
L is a bond or substituted or unsubstituted alkylene;
R 1 is —Nr 2 R 3 ;
R 2 and R 3 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein R 2 and R 3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
R 5 and R 6 are independently hydrogen or halogen;
or pharmaceutically acceptable salts thereof,
thereby modulating said activity of said FLT3-kinase.

55 . - 56 . (canceled)

57 . The method of claim 54 , wherein said FLT3-kinase is a FLT3-mutant kinase.

58 . The method of claim 57 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase.

59 . The method claim 58 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, 1836, D839, 5840, N841, or Y842 of SEQ ID NO:1.

60 . - 61 . (canceled)

62 . The method of claim 54 , wherein the method further comprises modulating STAT signaling, STAT3, STAT5, MAP kinase signaling, or AKT signaling.

63 . - 65 . (canceled)

Assignees

• Hope City

Inventors

• Nam Sangkil
• Horne David
• Xie Jun

Classifications

• C07D209/40 Primary

  Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone · CPC title